Myocardial infarction (MI) is the leading cause of death in the US. Those that survive, frequently go on to develop ventricular dysfunction and heart failure. While revascularization has dramatically reduced mortality after MI, ongoing efforts to develop post-MI cardioprotective therapies that prevent cardiomyocyte cell death have been unsuccessful. Here, we consider an alternative therapeutic approach, limiting the excessive and maladaptive innate immune response to cell death. When cells die, they release danger signals that overlap with the molecular features that our immune system uses to recognize pathogens. As a result, MI elicits strong innate immune responses. We found that IRF3, a master regulator of the antiviral response plays an unexpected essential role in the pathogenesis of MI. Mice deficient in IRF3 exhibited less inflammation and were strikingly protected from death after MI compared to wild type mice. We hypothesize that multiple cell types in the infarct and borderzone play unique roles in spreading IRF3-dependent signals, promoting immunologic infarct expansion, and increasing the risk of heart failure and death after MI. The scientific aims of this K99/R00 are to 1) identify which danger signaling pathway is responsible for activation of IRF3 after MI, 2) identify which cardiac cell type(s) are responsible for IRF3-mediated injury and death after MI, and 3) to develop pharmacologic inhibitors of IRF3 activation as a novel class of post-MI cardioprotectants. The longterm goal of these studies is to identify cardioprotectants that can be administered post-MI to limit ?immunologic infarct expansion? and development of chronic heart failure.